Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer’s disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA. The regulation of apoptotic cascades is complex and involves transcriptional control as well as posttranscriptional protein modifications, such as protease-mediated cleavage, ubiquitination or poly(ADP-ribosylation). More recently, the regulation of protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. A better understanding of the molecular underpinnings of neuronal apoptosis will lead to novel preventive and therapeutic approaches to the neurodegenerative processes in Alzheimer’s disease and other neurological disorders where programmed cell death is prominent.

Free radicals provide a generally accepted explanation for age-related decline in tissue function. However, the free radical hypothesis does not provide a mechanistic course of action to explain exactly how damage to macromolecules translates into the recognizable pathophysiology of aged organisms. Recent advances in the fields of DNA damage and cellular senescence point towards a substantial role for the DNA damage response, rather than DNA mutations per se, in the genesis of cellular and/or tissue damage. Furthermore, several studies suggest that protein damage can be at least as important as DNA damage in bringing about the aging phenotype. Here we propose that a “protein damage response,” namely the ER/UPR (endoplasmic reticulum/unfolded protein) stress response is likely to play an important role in the aging process.

Department of Pharmacology, University of California, Irvine, CA, USA. spduckle@uci.edu

Mitochondrial dysfunction has been implicated as a cause of age-related disorders, and the mitochondrial theory of aging links aging, exercise, and diet. Endothelial dysfunction is a key paradigm for vascular disease and aging, and there is considerable evidence that exercise and dietary restriction protect against cardiovascular disease. Recent studies demonstrate that estrogen receptors are present in mitochondria and that estrogen promotes mitochondrial efficiency and decreases oxidative stress in the cerebral vasculature. Chronic estrogen treatment increases mitochondrial capacity for oxidative phosphorylation while decreasing production of reactive oxygen species. The effectiveness of estrogen against age-related cardiovascular disorders, including stroke, may thus arise in part from hormonal effects on mitochondrial function. Estrogen-mediated mitochondrial efficiency may also be a contributing factor to the longer lifespan of women.

Part of the series: from dietary antioxidants to regulators in cellular signalling and gene expression. Role of reactive oxygen species and (phyto)oestrogens in the modulation of adaptive response to stress.

There is increasing evidence that reactive oxygen species (ROS) are not only toxic but play an important role in cellular signalling and in the regulation of gene expression. We, here, discuss two examples of improved adaptive response to an altered cellular redox state. First, differences in longevity between males and females may be explained by a higher expression of antioxidant enzymes in females resulting in a lower yield of mitochondrial ROS. Oestrogens are made responsible for these phenomena. Oestradiol induces glutathione peroxidase-1 and MnSOD by processes requiring the cell surface oestrogen receptor (ER) and the activation of pathways usually involved in oxidative stress response. Second, oxygen radicals produced during moderate exercise as performed during training up-regulate the expression of antioxidant enzymes in muscle cells. An increased level of these enzymes might prevent oxidative damage during exhaustive exercise and should, therefore, not be prevented by antioxidants. The relevance of these findings is discussed in the context with observations made in transgenic animals overexpressing MnSOD or catalase.

C. elegans SIR-2.1, a member of the Sir-2 family of NAD(+)-dependent protein deacetylases, has been shown to regulate nematode aging via the insulin/IGF pathway transcription factor daf-16. Treatment of C. elegans with the small molecule resveratrol, however, extends life span in a manner fully dependent upon sir-2.1, but independent of daf-16. Microarray analysis of worms treated with resveratrol demonstrates the transcriptional induction of a family of genes encoding prion-like glutamine/asparagine-rich proteins involved in endoplasmic reticulum (ER) stress response to unfolded proteins. RNA interference of abu-11, a member of this ER stress gene family, abolishes resveratrol-mediated life span extension, and overexpression of abu-11 extends the life span of transgenic animals. Furthermore, SIR-2.1 normally represses transcription of abu-11 and other ER stress gene family members, indicating that resveratrol extends life span by inhibiting sir-2.1-mediated repression of ER stress genes. Our findings demonstrate that abu-11 and other members of its ER stress gene family are positive determinants of C. elegans life span.

Energy restriction (ER) and dietary fish oil (FO) are known to reduce the severity of glomerulonephritis and increase the lifespan of lupus-prone (NZB x NZW) F1 (B/W) mice. In the present study, mice were fed either ad libitum or energy-restricted (a 40 % lower energy intake than the diet ad libitum), semi-purified diets containing 5 % maize oil or 5 % fish oil supplementation. To estimate the renal damage associated with oxidative stress, the total amounts of reactive oxygen species (ROS), cyclooxygenase-derived ROS and levels of guanidino compounds were measured. Additionally, we assessed the putative action of ER and FO on several key antioxidant enzymes measured in the kidney post-mitochondrial fraction. Results showed that the age-related increase in creatinine level was significantly reduced by ER and FO in old mice. In contrast, arginine and guanidino acetic acid levels showed a decrease with age but were increased by ER and FO. The GSH:GSSG ratio showed a significant decrease with age, whereas ER and FO feeding prevented the decrease. The age-related decrease in antioxidant scavenging superoxide dismutase, catalase and glutathione peroxidase activities were all reversed by ER and FO. The moderately decreased glutathione reductase and glutathione-S-transferase activities with age were significantly increased by ER and FO. Furthermore, the increased total ROS and cyclooxygenase-derived ROS levels were effectively reduced by ER and FO. In conclusion, our data strongly indicate that ER and FO maintain antioxidant status and GSH:GSSG ratio, thereby protecting against renal deterioration from oxidative insults during ageing.

Females live longer than males in many mammalian species, including humans. Mitochondria from females produce approximately half the amount of H(2)O(2) than males. We have found that females behave as double transgenics overexpressing both superoxide dismutase and glutathione peroxidase. This is due to oestrogens that act by binding to the estrogen receptors and subsequently activating the mitogen activated protein (MAP) kinase and nuclear factor kappa B (NF-kappaB) signalling pathways. Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of upregulating antioxidant genes, by hormonal and dietary manipulations, in order to increase longevity is discussed.

Aging is accompanied by the changes in the cells that decrease their capacity to respond to various forms of stress. Cells are known to respond to stresses through expression of stress-response proteins, heat-shock proteins composed of molecular chaperones. Recent studies suggest that chaperone level and stress-induced chaperone expression could decrease with aging. The aim of the present study is to identify chaperones that show a significant change in protein expression with aging. We used an in vitro aging model system of human diploid fibroblasts (HDF). Proteome analysis of HDF showed that endoplasmic reticulum (ER) chaperone, calnexin, significantly decreased with aging. Oxidative stress-induced expression of calnexin also attenuated in old HDF compared to young cells. These findings suggest calnexin decreases with aging and might contribute to a cytoprotection in a variety of human age-related diseases.

Since the work of McCay in 1935, demonstrating the effect of energy restricted diet on the lifespan of rats, many studies have confirmed these findings in different species. Several mechanisms have been suggested, including among others, growth retardation, diminished apoptosis, decreased oxidative damage, altered glucose utilization, changes in gene expression, enhanced stress responsiveness and hormesis. There is some evidence that energy restriction (ER) exerts important metabolic effects on the aging process and longevity through intra- and intercellular signal transduction transmitters, with several signaling pathways mediating its beneficial action. Copyright 2003 Elsevier Ireland Ltd.

Yale University School of Medicine, Department of Internal Medicine, Section of Geriatrics, New Haven, CT 06511, USA.

The endoplasmic reticulum (ER), as a processing plant for the folding and posttranslational modification of proteins, is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed ‘ER stress’, can perturb ER functions, leading to the activation of a complex response known as the unfolded protein response. Here, we investigated the response of hepatocytes derived from young (4-5 months) and aged (24-26 months) rats to two agents, thapsigargin (TG) and tunicamycin (TM), which act via different mechanisms to induce ER stress. Old hepatocytes displayed greater cell death than young cells following treatment with TG or TM, associated with higher expression of the pro-apoptotic gene gadd153 (also known as chop) and enhanced c-Jun N-terminal protein kinase (JNK) activation. Pharmacologic inhibition of JNK decreased the expression of TG-stimulated gadd153 in old cells and reduced their sensitivity to TG-induced cell death. Inhibition of p38, on the other hand, enhanced TG-induced gadd153 expression and JNK activation, and augmented TG-induced cell death. Additional experiments implicated the PERK/eIF-2 alpha signaling pathway as a contributor to the higher Gadd153 expression and JNK activation, and greater sensitivity of old cells to ER stress.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. jjramsey@ucdavis.edu

Energy restriction (ER), without malnutrition, is the only environmental intervention that consistently increases maximum life span in laboratory rodents. One theory proposes that a reduction in energy expenditure and reactive oxygen species production is the mechanism responsible for this action of ER. To further test this theory, proton leak, H2O2 production, lipid peroxidation, and protein carbonyls were measured in mitochondria from FBNF1 rats fed either a control or 40% ER diet (onset at 6 mo of age). Liver mitochondria were isolated at 7 and 12 mo of age. Liver weight decreased 25 and 36% at 1 and 6 mo of ER, respectively (P < 0.05). ER resulted in an increase (P < 0.05) in percent total polyunsaturates, n-6 polyunsaturates, and total unsaturates (6 mo only) in mitochondrial lipids. These changes, however, were not associated with significant alterations in mitochondrial function. State 4 respiration and membrane potential were not different (P > 0.05) between groups at either assessment period. Similarly, proton leak kinetics were not different between control and ER animals. Top-down metabolic control analysis and its extension, elasticity analysis, were used at the 6-mo assessment and revealed no difference in control of the oxidative phosphorylation system between control and ER rats. H2O2 production with either succinate or pyruvate/malate substrates was also not different (P > 0.05) between groups at either time point. In conclusion, ER did not alter proton leak or H2O2 production at this age or stage of restriction in liver.

Oxidatively modified proteins have been shown to correlate with the age of an organism or its tissues. An increase in tissue-susceptibility to experimentally induced protein oxidation not only depends on tissue type and age, but also on the maximum lifespan potential of the species. A general, although tissue dependent, decline in anti-oxidative defenses during aging may very well be responsible for this difference in vulnerability. In addition, the level of protein modifications also depends on the nature and the subcellular localization of the proteins involved. Damage to the endoplasmic reticulum (ER), and its subsequent impaired functionality may be involved in the process of aging. This is suggested by; (1) an upregulation of ER stress-response chaperones, (2) a preferential oxidation of ER-resident proteins and, (3) a disturbance of calcium homeostasis. Therefore, this review will focus on the putative involvement of the oxidized endoplasmic reticulum in the process of aging.

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